Table 1 Anti-Cryptosporidium activity, in vitro and in vivo parameters of soft drug and other compounds

From: Cryptosporidium PI(4)K inhibitor EDI048 is a gut-restricted parasiticidal agent to treat paediatric enteric cryptosporidiosis

Compound names

Anti-Cryptosporidium activity

Selectivity

In vitro PK

In vitro stability (M/H)

In vivo PKa

Cp CPE EC50 (µM)

Ch CPE EC50 (µM)

CpPI(4)K IC50 (µM)

HsPI(4)K IC50 (µM)

HepG2 CC50 (µM)

Solubility pH 6.8/FaSSIF (mM)

Permeability (×10−6 cm s−1) A–B/B–A/ratio

IS9 (T1/2, min)

Hepatocytes ER (%) (min)

Plasma (T1/2, min)

Cmax (nM)

AUCb (nM h)

KDU731

0.156 ± 0.028

0.207 ± 0.002

0.017 ± 0.008

1.935 ± 1.082

59.982 ± 0.000

0.019/0.048

1.95/15.49/7.93

>240/–

18/60 (>175/57.9)

85.2/>120

659

2,982

NTZ

18.837 ± 0.903

>20 ± 0.000

>10 ± 0.000

>30 ± 0.000

34.900 ± 0.000

–

–

–

–

–

2,080c

4,493c

1

0.071 ± 0.016

0.066 ± 0.000

0.007 ± 0.002

1.141 ± 0.296

14.747 ± 0.000

0.031/0.086

7.89/7.4/0.94

120/120

74/– (13.4/–)

13.6/>120

293 (1,656d)

1,184 (3,775d)

2

>20 ± 0.000

>20 ± 0.000

0.002 ± 0.000

0.135 ± 0.033

>100 ± 0.000

0.708/1.0

0.89/1.65/1.85

>240/–

52/– (35.8/–)

>120/>120

50

–e

3

>20 ± 0.000

>20 ± 0.000

0.005 ± 0.000

1.034 ± 0.485

38.228 ± 0.000

0.011/0.355

–

9.2/45

93/– (<2.8/–)

–

<LLOQf

<LLOQf

4

0.349 ± 0.181

0.503 ± 0.053

0.018 ± 0.011

1.380 ± 0.130

32.249 ± 0.000

0.037/–

–

96/215

–/95 (–/4.8)

<5/>120

31.7

75

5

0.039 ± 0.008

0.032 ± 0.001

0.005 ± 0.002

0.203 ± 0.047

>100 ± 0.000

0.110/0.147

2.55/15.65/6.15

60/106

91/– (4/–)

>120/>120

32.7

142

EDI048

0.052 ± 0.013

0.050 ± 0.001

0.004 ± 0.002

1.032 ± 0.470

28.083 ± 0.000

0.054/0.198

7.92/12.86/1.62

45/235

93/97 (2.8/<3)

15.3/>120

8.4 (33.4g)

19 (73.4g)

6

>20 ± 0.000

ND

0.031 ± 0.024

0.484 ± 0.119

>100 ± 0.000

>1/–

0.56/1.04/1.86

>240/–

18/33 (>175/>175)

–

–

–

7

>20 ± 0.000

ND

0.076 ± 0.000

11.25 ± 0.00

>100 ± 0.000

–

–

–

–

–

–

–

  1. Data shown are mean ± s.e.m., n = 3 biological replicates for most of the in vitro data. M/H, mouse/human; ND, not determined; LLOQ, lower limit of quantification; Cp, C. parvum; Ch, C. hominis; FaSSIF, fasted state simulated intestinal fluid; A–B, apical to basolateral; ratio, B–A/A–B; ER, extraction ratio.
  2. aIn vivo PK from the mouse efficacy studies with 10 mg kg−1 oral dosing except Nitazoxanide dosed at 100 mg kg−1.
  3. bAUC is area under the curve from time 0 to the last timepoint measured.
  4. cPK parameters are for active metabolite Tizoxanide following Nitazoxanide dosing at 100 mg kg−1.
  5. dCompound 2 systemic concentrations following Compound 1 dosing.
  6. eNot calculable (except at Cmax concentration, all other timepoints were below limit of quantification, 10.8 nM for Compound 2).
  7. fAll concentrations were below limit of quantification, 8.9 nM for Compound 3.
  8. gCompound 6 systemic concentration following EDI048 dosing.
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